Project Summary Given that many of the most common fracture sites, such as those of the distal radius and vertebrae, are predominantly trabecular, the prevailing view is that osteoporotic fractures primarily result from decreased density and impaired structural integrity of trabecular bone. However, 80% of the skeleton consists of cortical bone and some of the most devastating fractures, such as those of the femoral neck, occur at a location where the stresses are shared by the two types of bone. Hormonal loss following menopause causes enhanced cortical remodeling leading to increased pore volume fraction caused by expansion of Haversian and Volkman canals and formation of composite osteons. Paralleling these processes is a decrease in mineralization, referred to as degree of mineralization of bone (DMB), due to the bone's failure of undergoing secondary mineralization. Both effects have previously been shown to be modifiable and partially reversible by treatment with antiresorptive drugs as assessed with measurements in iliac bone biopsy specimens. In preliminary studies leading up to this project, we conceived new quantitative solid-state 1H and 31P MRI methods based on zero-echo-time (ZTE) PETRA encoding and new non-iterative reconstruction techniques for evaluating measures of cortical porosity and mineral density, thereby delineating a path toward noninvasive assessment of cortical bone ultrastructure and chemistry. The approach chosen makes use of T2-selective suppression pulses providing pore and collagen-bound water. The latter is shown to represent a surrogate for bone tissue matrix density yielding, along with 31P density, DMB. In this competing renewal application we propose to reduce to practice, validate, and translate these methods to patient studies. Our primary hypothesis is that postmenopausal women with osteoporosis (OP) have greater cortical porosity as assessed by 1H MRI surrogate markers than their healthy peers; and further that porosity in these patients decreases upon antiresorptive treatment. Our secondary hypothesis is that OP subjects have lower DMB as measured by 31P MRI surrogate markers, and that antiresorptive treatment increases DMB. We propose to evaluate these hypotheses with an integrated MRI protocol in a cohort of OP women in comparison to matched healthy controls, both at baseline and after 12 and 24 months of alendronate treatment. We expect the outcome to show that the proposed technology can quantify and distinguish inter-group differences of the parameters measured, both at baseline and in response to intervention. The proposed comprehensive quantitative MR imaging protocol, which can readily be implemented on standard clinical MRI equipment, should yield new insight into microstructure and mineral properties of cortical bone, and provide new ways to evaluate the response to antiresorptive treatment in patients.